The adverse effects of illicit drug use result from both direct toxicities and indirect effects due to infections, non-adherence to medical regimens, poor nutrition, and impaired self- care. These adverse effects are especially evident in HIV-infected individuals due to their high prevalence of comorbid conditions and physiologic frailty. Effective treatment of substance use disorders leading to reductions in illicit drug use can influence physiology in an equally diverse manner by reducing direct toxicities and improving medication adherence, nutrition and self-care. Therefore the health benefits of drug treatment not captured by self-report of illicit drug use or urine toxicology analyses, may be better reflected by markers of liver, hematologic, kidney, and immune function. The Veterans Aging Cohort (VACS) Index adds measures of liver (hepatitis C infection, FIB- 4), kidney (eGFR), and hematologic (hemoglobin, platelets) function to age, CD4 count and HIV viral load and is a validated biomarker index that has been shown to reflect improvement in immune function, alcohol consumption, and overall health in HIV- infected patients. The goals of the proposed research are to evaluate the VACS Index as a biomarker reflecting the benefits of reductions of substance use in a series of three sub studies. Aim 1 will be conducted in HIV-infected opioid dependent individuals receiving opioid agonist treatment. Changes in illicit opioid use assessed using urine toxicology analyses will be correlated with changes in the VACS Index. Aim 2 will correlate changes in self-reported use of individual substances (opioids, cocaine, marijuana, and tobacco) among HIV-infected subjects, with changes in the VACS Index and compare VACS Index results obtained during periods of drug use, with those obtained during periods of abstinence. Aim 3 will evaluate the responsiveness of a modified VACS Index (removing CD4 count and HIV viral load) to changes in opioid use, assessed using urine toxicology analysis, among HIV-uninfected individuals receiving opioid agonist treatment. This line of research conducted in a large and well characterized cohort of HIV-infected and HIV-uninfected patients with extensive data on laboratory values, urine toxicology tests, and medication-assisted treatment, will add to the extensive validation work we have done with the VACS Index. This work has the potential to provide evidence supporting the use of this unique aggregation of commonly available laboratory tests to monitor the health benefits of reduced illicit drug use.